Endothelial senescence alleviates cognitive impairment in a mouse model of Alzheimer's disease

Aug 23, 2023Glia

Aging of blood vessel lining cells may reduce memory problems in a mouse model of Alzheimer's disease

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Abstract

APP/PS1;TERF2DN mice exhibited a reduction in cognitive impairment and amyloid-β pathology compared to control APP/PS1 mice.

Endothelial cell senescence is present in the brains of Alzheimer's disease models.
The APP/PS1;TERF2DN mouse model showed compaction of amyloid-β plaques and increased microglial coverage.
Microglia in TERF2DN-Tg mice had more processes and enhanced phagocytosis of amyloid-β.
Single-cell RNA sequencing revealed a modest decrease in disease-associated microglia in APP/PS1;TERF2DN mice.
These findings suggest that endothelial cell senescence may promote a protective microglial phenotype.

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Alzheimer's disease (AD) is among the most prevalent age-related neurodegenerative diseases. Endothelial cell (EC) senescence was discovered in the AD brain, but its function in AD pathogenesis was unidentified. Here we created an AD mouse model with EC senescence (APP/PS1;TERF2DN mice) by intercrossing APP/PS1 mice with Tie2 promoter-driven dominant negative telomeric repeat-binding factor 2 transgenic mice (TERF2DN-Tg mice). We evaluated cognitive functions and AD brain pathology in APP/PS1;TERF2DN mice. Surprisingly, compared with the control APP/PS1 mice, APP/PS1;TERF2DN mice demonstrated the attenuation of cognitive impairment and amyloid-β (Aβ) pathology, accompanied by the compaction of Aβ plaques with increased microglial coverage and reduced neurite dystrophy. Moreover, we evaluated whether EC senescence could affect microglial morphology and phagocytosis of Aβ. Compared with wild-type mice, microglia in TERF2DN-Tg mice display increased numbers of endpoints (a morphometric parameter to quantify the number of processes) and Aβ phagocytosis and related gene expression. Single-cell RNA-sequencing analysis showed that compared with APP/PS1 mouse microglia, APP/PS1;TERF2DN mouse microglia displayed a modest decline in disease-associated microglia, accompanied by an altered direction of biological process branching from antigen synthesis and arrangement to ribonucleoprotein complex biogenesis. Our outcomes indicate that EC senescence alters microglia toward a protective phenotype with a rise in phagocytic and barrier roles, and may offer a clue to create a novel preventive/therapeutic method to treat AD.

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Endothelial senescence alleviates cognitive impairment in a mouse model of Alzheimer's disease

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